Categories: Synthesis of N-Heterocycles >
Synthesis of pyrroles
An operationally simple, practical, and economical Paal-Knorr pyrrole condensation of 2,5-dimethoxytetrahydrofuran with various amines and sulfonamines in water in the presence of a catalytic amount of iron(III) chloride allows the synthesis of N-substituted pyrroles under very mild reaction conditions in good to excellent yields.
N. Azizi, A. Khajeh-Amiri, H. Ghafuri, M. Bolourtchian, M. R. Saidi, Synlett, 2009, 2245-2248.
A method for the preparation of N-acylpyrroles involves condensation of carboxylic acids with 2,4,4-trimethoxybutan-1-amine, followed by acid-mediated cyclization to form the pyrrole ring. The preparative procedure is highly tolerant of various functional groups.
T. Maehara, R. Kanno, S. Yokoshima, T. Fukuyama, Org. Lett., 2012, 14, 1946-1948.
Acid chlorides can be activated to transient acid iodide intermediates using a simple iodide source. This indermediates undergo nucleophilic attack from a variety of relatively weak nucleophiles - including Friedel-Crafts acylation of N-methylpyrroles, N-acylation of sulfonamides, and acylation reactions of hindered phenol derivatives.
R. J. Wakeham, J. E. Taylor, S. D. Bull, J. A. Morris, J. M. J. Williams, Org. Lett., 2013, 15, 702-705.
A highly efficient Cu-catalyzed tandem C-N bond-forming reaction of 1,4-dihalo-1,3-dienes allows the synthesis of pyrroles and heteroarylpyrroles with a wide variety of functional groups and substitution patterns from readily available precursors.
R. Martín, C. H. Larsen, A. Cuenca, S. L. Buchwald, Org. Lett., 2007, 9, 3379-3382.
An efficient copper-catalyzed double alkenylation of amides with (1Z,3Z)-1,4-diiodo-1,3-dienes affords di- or trisubstituted N-acylpyrroles in good yields using CuI as the catalyst, Cs2CO3 as the base, and rac-trans-N,N'-dimethylcyclohexane-1,2-diamine as the ligand.
X. Yuan, X. Xu, X. Zhou, J. Yuan, L. Mai, Y. Li, J. Org. Chem., 2007, 72, 1510-1513.
A tandem reaction involving cross metathesis followed by concomitant cyclisation enables the synthesis of substituted pyrroles. Various protected electron-deficient N-allylamines reacted with α,β-unsaturated carbonyl compounds in the presence of Lewis acids under the cross metathesis conditions using a 2nd generation Hoveyda catalyst in order to form pyrroles.
S. Shafi, M. Kędziorek, K. Grela, Synlett, 2011, 124-128.
Titanium-catalyzed intermolecular hydroaminations enabled efficient, user-friendly one-pot reactions for the preparations of 2-substituted and fully substituted pyrroles from (E/Z)-chloroenynes and easily accessible α-haloalkynols, respectively.
L. Ackermann, R. Sandmann, L. T. Kaspar, Org. Lett., 2009, 11, 2031-2034.
Nucleophilic addition of sulfonamides to 1-bromo-1-alkynes provided (Z)-N-(1-bromo-1-alken-2-yl)-p-toluenesulfonamides in good yield and in a highly regio- and stereoselective manner. A subsequent reaction in the presence of a palladium catalyst under Heck conditions afforded substituted pyrroles in good yield.
M. Yamagishi, K. Nishigai, T. Hata, H. Urabe, Org. Lett., 2011, 13, 4873-4875.
A facile and efficient protocol enabled the synthesis of 1,2,4-substituted pyrrole derivatives from ready available starting materials. This type of reaction should have potential utility in organic synthesis.
D. Zhu, J. Zhao, Y. Wei, H. Zhou, Synlett, 2011, 2185-2186.
Intramolecular cyclizations of 3-alkyne-1,2-diols and 1-amino-3-alkyn-2-ols with very low catalyst loading of (Ph3P)AuCl-AgNTf2 or (Ph3P)AuCl-AgOTf proceeded at room temperature to provide various substituted furans and pyrroles in excellent yields. This method was also fully applicable to the conversion of 26 g of a substrate using only 0.05 mol % each of the Au and Ag catalysts.
M. Egi, K. Azechi, S. Akai, Org. Lett., 2009, 11, 5002-5005.
Copper or nickel catalyzed highly selective denitrogenative annulations of vinyl azides with aryl acetaldehydes afford 2,4- and 3,4-diaryl substituted pyrroles depending on the selection of the transition metal catalyst. Compared with the reported acidic or basic conditions for polysubstituted pyrrole synthesis, the reaction conditions are mild, neutral, and very simple without any additives.
F. Chen, T. Shen, Y. Cui, N. Jiao, Org. Lett., 2012, 14, 4926-4929.
Manganese(III)-catalyzed formal [3+2] annnulation of vinyl azides and β-keto acids enables the synthesis of substituted NH pyrroles with a wide range of substituents.
E. P. J. Ng, Y.-F. Wang, S. Chiba, Synlett, 2011, 783-786.
Furans, pyrroles, and thiophenes are efficiently and conveniently prepared by gold-catalyzed dehydrative cyclizations of readily available, heteroatom-substituted propargylic alcohols. The reactions provide essentially pure aromatic heterocycles in high yields in minutes under open-flask conditions with low catalyst loadings.
A. Aponick, C.-Y. Li, J. Malinge, E. F. Marques, Org. Lett., 2009, 11, 4624-4627.
A convenient and general one-pot synthesis of substituted pyrroles from propargylic acetates, silyl enol ethers, and primary amines was catalyzed by indium trichloride. High yields of various pyrrole derivatives were obtained.
M. Lin, L. Hao, R.-d. Ma, Z.-p. Zhan, Synlett, 2010, 2345-2351.
Highly substituted furans were conveniently synthesized by the platinum-catalyzed reaction of propargylic oxiranes. Propargylic aziridines were also reacted with the platinum catalyst to produce the corresponding substituted pyrroles in good yields.
M. Yoshida, M. Al-Amin, K. Shishido, Synthesis, 2009, 2454-2466.
Aryl-substituted N-tosyl alkynyl aziridines undergo a gold-catalyzed ring expansion to afford 2,5-substituted pyrrole products. Depending on the the counterion to the gold catalyst and the solvent, a ring-expansion and rearrangement leads to 2,4-substituted pyrroles.
P. W. Davies, N. Martin, Org. Lett., 2009, 11, 2293-2296.
(Hetero)aryl-, alkenyl-, and selected alkyl-substituted acid chlorides can be efficiently coupled with N-Boc-protected propargylamine to produce ynones which are converted to 2-substituted N-Boc-4-iodopyrroles in a one-pot reaction. Upon addition of a further alkyne, another Sonogashira coupling can be carried out in a one-pot fashion.
E. Merkul, C. Boersch, W. Frank, T. J. J. Müller, Org. Lett., 2009, 11, 2269-2272.
The use 10 mol % of Cu(OTf)2 enables the coupling of α-diazoketones with β-enaminoketones and esters to yield 2,4,5-trisubstituted pyrrole derivatives. A wide range of 2,3-disubstituted indole derivatives were also prepared from α-diazoketones and 2-aminoaryl or alkyl ketones.
B. V. S. Reddy, M. R. Reddy, Y. G. Rao, J. S. Yadav, B. Srighar, Org. Lett., 2013, 15, 464-467.
A range of 2,5-disubstituted and 2,4,5-trisubstituted pyrroles can be synthesized from dienyl azides at room temperature using ZnI2 or Rh2(O2CC3F7)4 as catalysts.
H. Dong, M. Shen, J. E. Redford, B. J. Stokes, A. L. Pumphrey, T. G. Driver, Org. Lett., 2007, 9, 5191-5194.
An efficient, solvent-free, microwave-assisted coupling of chloroenones and amines on the surface of silica gel gave 1,2-disubstituted homochiral pyrroles in good yields.
F. Aydogan, A. S. Demir, Tetrahedron, 2005, 61, 3019-3023.
The CuI/N,N-dimethylglycine-catalyzed reaction of amines with γ-bromo-substituted γ,δ-unsaturated ketones in the presence of K3PO4 and NH4OAc gave the corresponding polysubstituted pyrroles in very good yields.
Y. Pan, H. Lu, Y. Fang, X. Fang, L. Chen, J. Qian, J. Wang, C. Li, Synthesis, 2007, 1242-1246.
A mild, gold(I)-catalyzed acetylenic Schmidt reaction of homopropargyl azides gave regiospecific substituted pyrroles. A mechanism in which azides serve as nucleophiles toward gold(I)-activated alkynes with subsequent gold(I)-aided expulsion of dinitrogen is proposed.
D. J. Gorin, N. R. Davis, F. D. Toste, J. Am. Chem. Soc., 2005, 127, 11260-11261.
A mild, gold(I)-catalyzed cycloisomerization of β-allenylhydrazones provides an efficient access to multisubstituted N-aminopyrroles in good to excellent yields with short reaction times through a selective intramolecular 1,2-alkyl or -aryl migration. This intramolecular cyclization can be applied either to alkyl- or aryl-substituted allenes.
E. Benedetti, G. Lemière, L.-L. Chapellet, A. Penoni, G. Palmisano, M. Malacria, J.-P. Goddard, L. Fensterband, Org. Lett., 2010, 12, 4396-4399.
A one-step reaction to assemble pyrroles from α,β-unsaturated imines and acid chlorides is mediated by triphenylphosphine, which eliminates phosphine oxide to allow cyclization. This reaction has been employed to access broad range of pyrroles via modulation of the two building blocks and applied as well to the synthesis of lukianol A.
Y. Lu, B. A. Arndtsen, Org. Lett., 2009, 11, 1369-1372.
An iron(III)-catalyed four-component coupling reactions of 1,3-dicarbonyl compounds, amines, aromatic aldehydes, and nitroalkanes without an inert atmosphere provides highly substituted pyrroles in good yields. Notably, this method is very cheap, straightforward, and environmentally friendly compared to existing methods.
S. Maiti, S. Biswas, U. Jana, J. Org. Chem., 2010, 75, 1674-1683.
The FeCl3-catalyzed addition and cyclization of enamino esters with nitroolefins provides a rapid, straightforward, and general method for the synthesis of tetrasubstituted NH pyrroles in good yields and tolerates a wide range of functionality. Further, an efficient KOAc-promoted addition and cyclization protocol provides substituted furans as well.
L. Li, M.-N. Zhao, Z.-H. Ren, J. Li, Z.-H. Guan, Synthesis, 2012, 44, 532-540.
A fast, mild, and environmentally benign domino reaction enables an efficient reaction of (E)-β-bromonitrostyrenes with enaminones in water to afford pyrroles in excellent yields.
M. Rueping, A. Parra, Org. Lett., 2010, 12, 5281-5283.
An efficient rhodium-catalyzed rearrangement of α-oximino ketenes derived from α-diazo oxime ethers provides 2H-azirines bearing quaternary centers and allows for subsequent rearrangement to highly substituted pyrroles in excellent yields.
Y. Jiang, W. C. Chan, C.-M. Park, J. Am. Chem. Soc., 2012, 134, 4104-4107.
A cationic N-heterocyclic carbene-gold(I) complex catalyzes the formation of tri- and tetrasubstituted pyrroles from N-propargyl β-enaminone derivatives via an amino-Claisen rearrangement to yield α-allenyl β-enaminones and subsequent cyclization of these intermediates.
A. Saito, O. Konishi, Y. Hanzawa, Org. Lett., 2010, 12, 372-374.
N-Propargylic β-enaminones are common intermediates for the synthesis of polysubstituted pyrroles and pyridines. In the presence of Cs2CO3 N-propargylic β-enaminones are cyclized to pyrroles in good to high yields, whereas CuBr leads to pyridines.
S. Cacchi, G. Fabrizi, E. Filisti, Org. Lett., 2008, 10, 2629-2632.
Various 2-alkyl-5-aryl-(1H)-pyrrole-4-ol derivatives were synthesized via a multicomponent reaction of β-dicarbonyl compounds with arylglyoxals in the presence of ammonium acetate in water at room temperature.
B. Khalili, P. Jajarmi, B. Eftekhari-Sis, M. M. Hashemi, J. Org. Chem., 2008, 73, 2090-2095.
An efficient and regioselective palladium-catalyzed cyclization of internal alkynes and 2-amino-3-iodoacrylates gave good yields of highly functionalized pyrroles.
M. L. Crawley, I. Goljer, D. J. Jenkins, J. F. Mehlmann, L. Nogle, R. Dooley, P. E. Mahaney, Org. Lett., 2006, 8, 5837-5840.
In(OTf)3 or In(NTf2)3 effectively catalyze the cycloisomerization reaction of α-propargyl-β-keto esters and their imine analogues to afford trisubstituted furans and pyrroles, respectively. Both terminal and internal alkynes take part in the reaction with good functional-group compatibility in the presence of only a small catalyst loading.
H. Tsuhi, K.-i. Yamagata, Y. Ueda, E. Nakamura, Synlett, 2011, 1015-1017.
A Mn(III)-catalyzed reaction of vinyl azides with 1,3-dicarbonyl compounds gave a broad range of polysubstituted N-H pyrroles in good yields.
Y.-F. Wang, K. K. Toh, S. Chiba, K. Narasaka, Org. Lett., 2008, 10, 5019-5022.
Two methods for the regioselective synthesis of tetra- and trisubstituted N-H pyrroles from starting vinyl azides have been developed: A thermal pyrrole formation via the 1,2-addition of 1,3-dicarbonyl compounds to 2H-azirine intermediates generated in situ from vinyl azides and a Cu(II)-catalyzed synthesis with ethyl acetoacetate through a 1,4-addition.
S. Chiba, Y.-F. Wang, G. Lapointe, K. Narasaka, Org. Lett., 2008, 10, 313-316.
A three-component reactions of arylacyl bromides, amines, and dialkyl acetylenedicarboxylate in the presence of iron(III) chloride as a catalyst at room temperature afforded polysubstituted pyrroles in high yields.
B. Das, G. C. Reddy, P. Balasubramanyam, B. Veeranjaneyulu, Synthesis, 2010, 1625-1628.
A simple, efficient, cost-effective, and metal-free four-component coupling reaction of aldehydes, amines, dialkyl acetylenedicarboxylates, and nitromethane furnished the corresponding 1,2,3,4-tetrasubstituted pyrroles under reflux in the presence of molecular iodine as a catalyst in high yields within 8 hours.
B. Das, N. Bhunia, M. Lingaiah, Synthesis, 2011, 3471-3474.
A new and efficient three-component reaction between dialkyl acetylenedicarboxylates, aromatic amines, triphenylphosphine, and arylglyoxals afforded polysubstituted pyrrole derivatives in high yields. The reactions were performed in dichloromethane at room temperature and under neutral conditions.
M. Anary-Abbasinejad, K. Charkhati, H. Anaraki-Ardakani, Synlett, 2009, 1115-1117.
A reaction between dialkyl acetylenedicarboxylates and β-aminoketones promoted by triphenylphosphine allows an efficient one-pot synthesis of polysubstituted 2,5-dihydropyrrole derivatives. The prepared 2,5-dihydropyrroles can be easily oxidized to the corresponding pyrrole derivatives with chromium trioxide.
M. Anary-Abbasinejad, E. Poorhassan, A. Hassanabadi, Synlett, 2009, 1929-1932.
A basic functionalized ionic liquid, 1-butyl-3-methylimidazolium hydroxide ([bmim]OH), catalyzed the three-component condensation reaction of acid chlorides, amino acids, and dialkyl acetylenedicarboxylates in water to afford functionalized pyrroles in high yields.
I. Yavari, E. Kowsari, Synlett, 2008, 897-899.
The reaction of an enaminone, which can be derived from two primary amines and diketene, in the presence of nitrostyrene gives functionalized pyrrole derivatives in very good yields.
A. Alizadeh, A. Rezvanian, H. R. Bijanzadeh, Synthesis, 2008, 725-728.
A silver(I)-promoted oxidative cyclization of homopropargylamines at room temperature provides pyrroles. Homopropargylamines are readily available by the addition of a propargyl Grignard reagent to Schiff bases.
S. Aggarwal, H.-J. Knölker, Org. Biomol. Chem., 2004, 2, 3060-3062.
A general, highly flexible Cu-catalyzed domino C-N coupling/hydroamination reaction constitutes a straightforward alternative to existing methodology for the preparation of pyrroles and pyrazoles.
R. Martin, M. R. Rivero, S. L. Buchwald, Angew. Chem. Int. Ed., 2006, 45, 7079-7082.
An efficient and highly versatile microwave-assisted Paal-Knorr condensation of various 1,4-diketones gave furans, pyrroles and thiophenes in good yields. In addition, transformations of the methoxycarbonyl moiety, such as Curtius rearrangement, hydrolysis to carboxylic acid, or the conversion into amine by reaction with a primary amine in the presence of Me3Al, are described.
G. Minetto, L. F. Raveglia, A. Sega, M. Taddei, Eur. J. Org. Chem., 2005, 5277-5288.
A direct synthesis of pyrroles from imines, acid chlorides, and alkynes mediated by isocyanides proceeds with a range of substrates, providing a method to generate various pyrroles in high yield. Mechanistic studies suggest a generation of imino analogues of münchnones, which can undergo in situ coupling with alkynes to liberate isocyanate and form the pyrrole product.
D. J. St. Cyr, N. Martin, B. A. Arndtsen, Org. Lett., 2007, 9, 449-452.
The nucleophilic addition of sodium azide to 1,2-allenyl esters regio- and stereoselectively generates vinyl azides in excellent yields. A sequential reaction for the synthesis of pyrroles using 1-allyllic 1,2-allenyl esters as substrates is developed on the basis of a domino process involving nucleophilic addition, cycloaddition, denitrogenation, and aromatization.
X. Huang, R. Shen, T. Zhang, J. Org. Chem., 2007, 72, 1534-1537.
The synthesis of N-acylpyrroles from primary aromatic amides and excess 2,5-dimethoxytetrahydrofuran in presence of one equivalent of thionyl chloride offers short reaction times, mild reaction conditions, and easy workup.
A. R. Ekkati, D. K. Bates, Synthesis, 2003, 1959-1961.
Propargyl vinyl ethers and aromatic amines are effectively converted into tetra- and pentasubstituted 5-methylpyrroles through a silver(I)-catalyzed propargyl-Claisen rearrangement, an amine condensation, and a gold(I)-catalyzed 5-exo-dig heterocyclization in a convenient one-pot process.
J. T. Binder, S. F. Kirsch, Org. Lett., 2006, 8, 2151-2153.
Various 2,3,4-trisubstituted pyrroles are easily accessible in one step from readily available acetylenes and acceptor-substituted methyl isocyanides by base-mediated or copper-catalyzed cycloadditions. Scope and limitations of both pyrrole syntheses are discussed.
O. V. Larionov, A. de Meijere, Angew. Chem. Int. Ed., 2005, 44, 5664-5667.
A novel and efficient multicomponent reaction of N-tosylimines, DMAD, and isocyanides for the synthesis of 2-aminopyrrole systems was uncovered.
V. Nair, A. U. Vinod, C. Rajesh, J. Org. Chem., 2001, 66, 4427-4429.
A Au(I)-catalyzed hydroamination or hydration of 1,3-diynes allows access to 2,5-diamidopyrroles and 2,5-diamidofurans. This method can also be expanded to 2,5-disubstituted furans and 1,2,5-trisubstituted pyrroles.
S. Kramer, J. L. H. Madsen, M. Rottländer, T. Skrydstrup, Org. Lett., 2010, 12, 2758-2761.
A robust and operational simple route to 2,4-disubstituted pyrrole heterocycles relying upon a cascade reaction is air and moisture tolerant and is performed at ambient temperature. Control over the reaction conditions provides ready access to isopyrroles, 2,3,4-trisubstituted pyrroles and 3-substituted pyrollidin-2-ones.
B. M. Trost, J.-P. Lumb, J. M. Azzarelli, J. Am. Chem. Soc., 2011, 133, 740-743.
A new microwave-assisted rearrangement of 1,3-oxazolidines scaffolds is the basis for a new, metal-free, direct, and modular construction of tetrasubstituted pyrroles from terminal-conjugated alkynes, aldehydes, and primary amines under very simple and environmental-friendly experimental conditions.
D. Tejedor, D. González-Cruz, F. García-Tellado, J. J. Marrero-Tellado, M. L. Rodríguez, J. Am. Chem. Soc., 2004, 126, 8390-8391.
Coupling of acetylene, nitrile, and a titanium reagent generated new azatitanacyclopentadienes in a highly regioselective manner. The subsequent reaction with sulfonylacetylene and electrophiles gave substituted pyridines virtually as a single isomer. Alternatively, the reaction of azatitanacyclopentadienes with an aldehyde or another nitrile gave furans or pyrroles having four different substituents again in a regioselective manner.
D. Suzuki, Y. Nobe, R. Tanaka, Y. Takayama, F. Sato, H. Urabe, J. Am. Chem. Soc., 2005, 127, 7474-7479.
An efficient synthesis of 2,3,4-trisubstituted pyrroles via intermolecular cyclization of alkylidenecyclopropyl ketones with amines was observed. A mechanism involving a distal cleavage of the C-C bond of the cyclopropane ring is discussed.
L. Lu, G. Chen, S. Ma, Org. Lett., 2006, 8, 835-838.
Several aryl-substituted pyrrole derivates were prepared conveniently in a microwave-assisted one pot-reaction from but-2-ene-1,4-diones and but-2-yne-1,4-diones via Pd/C-catalyzed hydrogenation of the carbon-carbon double bond/triple bond followed by amination-cyclization.
H. S. P. Rao, S. Jothilingam, H. W. Scheeren, Tetrahedron, 2004, 60, 1625-1630.
1,3,4-triaryl-2,5-dihydropyrroles were synthesized using the McMurry coupling reaction as key step. A facile and reliable non-catalytic photoconversion of 1,3,4-triaryl-2,5-dihydropyrroles furnished 1,3,4-triarylpyrroles in good yields.
D. X. Zeng, Y. Chen, Synlett, 2006, 490-492.
1-Vinylpyrroles are formylated by the N,N-dimethylformamide/oxalyl chloride reagent system to give the corresponding 1-vinylpyrrole-2-carbaldehydes in good yields in short reaction times.
A. I. Mikhaleva, A. V. Ivanoc, E. V. Skital'tseva, I. A. Ushakov, A. M. Vasil'tsov, B. A. Trofimov, Synthesis, 2009, 587-590.